Safe for HPV-negative women age 40 and over, Dutch study shows

Action Points

Extending the interval for cervical cancer screening tests from 5 to 10 years is safe for women age 40 or over who have tested negative for human papillomavirus (HPV).

Note that the study results support the upcoming change in the Netherlands screening program that extends the interval between screenings from 5 to 10 years for HPV-negative women age 40 and above.

Extending the interval for cervical cancer screening tests from 5 to 10 years is safe for women age 40 or over who have tested negative for human papillomavirus (HPV), according to Dutch investigators.

This supports the upcoming change in the Netherlands screening program that extends the interval between screenings from 5 to 10 years for HPV-negative women age 40 and above.

In the study the authors assessed the 14-year risk of histology-confirmed cervical cancer and cervical intraepithelial neoplasia grade 3 or worse (CIN3+) in women age 29-61 participating in the POBASCAM (Population-Based Screening Study Amsterdam) randomized controlled trial. The follow-up of 14 years included three screenings -- baseline, and after 5 and 10 years.

Women were randomly assigned to receive both HPV and cytology testing (the intervention group) or cytology testing only (the control group), and the authors compared the incidences of cervical cancer and CIIN3+ among HPV-negative women in the intervention group and cytology-negative women in the control group.

The cumulative incidence of cervical cancer and CIN3+ was 0.09% and 0.56%, respectively, among HPV-negative women in the intervention group after three rounds of screening (one round every 5 years), similar to the cumulative rates of 0.09% and 0.69%, respectively, among women with negative cytology in the control group.

After the third round of screening, the incidence of cervical cancer among HPV-negative and double-negative women in the intervention group was similar to that of the cytology-negative women in the control group -- risk ratio (RR) 0.97 (95% CI 0.41-2.31), P=0.95; 0.83 (0.32-2.15), P=0.69.

Also after three rounds of screening, the incidence of CIN3+ among HPV-negative and double-negative women from the intervention group was slightly lower than that of cytology-negative women from the control group at the second round (RR 0.82 [0.62.to 1.09], P=0.17; 0.76 [0.57 to 1.03], P=0.07).

"Our data indicate that good safety for both cervical cancer and CIN3+ risk is provided by extending the [screening] interval from 5 to 10 years, because the risks after three screening rounds after a negative HPV test are similar to the risks after two rounds after negative cytology," the authors wrote.

They pointed out that in the Netherlands, the changes in the HPV-based screening program will be extended only to women age 40 and older and that the study results support this age-specific recommendation -- specifically that the CIN+3 risk in that age group was estimated to be 72% lower than in younger women and that no significant association between cervical cancer incidence and age could be demonstrated.

"Despite our analyses, the risk of an increase in interval cancers remains a point of concern. Controlling both cervical cancer and CIN3+ risks is reassuring, but an increase in the cancer risk cannot be ruled out completely as long as the interval has not actually been extended," the authors wrote. "Therefore, it remains important to closely monitor the number of interval cancers observed under the new HPV-based screening [program]."

Dijkstra and her colleagues also noted that their analysis found that CIN3+ incidence among HPV-positive women with negative cytology, HPV 16/18 genotyping, and/or repeat cytology was 10.4 (95% CI 5.9 t0 18.4) times higher than among HPV-negative women. These results suggest that HPV-based programs with screening intervals of at least 5 years should be implemented with risk stratification, they said.

The United States Preventive Services Task Force recommends screening for cervical cancer in women age 21 to 65 with cytology, or for women age 30 to 65, to have screening with a combination of cytology and HPV testing every 5 years. These recommendations essentially mirror the guidelines put out by the American Cancer Society, the American Society for Clinical Pathology, the American Society for Colposcopy and Cervical Pathology, and the American Congress of Obstetricians and Gynecologists.

Asked for her opinion, Diane Harper, MD, MPH, professor and chair of the Department of Family and Geriatric Medicine at the University of Louisville in Kentucky, called the study by Dijkstra et al "the best designed and followed population-based study for cervical cancer screening of any ever reported."

"Their strong results of 14 years of follow-up of a captive population where cytology, histology, and HPV testing was centralized and well controlled clearly shows that women are best served by primary HPV testing, not co-testing," she told MedPage Today.

"This elegant study shows that women who are 40 years and older and negative for 14 high-risk HPV types have a very low risk of cervical cancer or CIN 3 and can be safely screened every 10 years. The 14 years of follow-up after a negative HPV test are rigorously evaluated to measure the effect of interval cancers developing within the 10-year screening time frame -- the interval development of cervical cancer was as close to zero as any screening technique and frequency has ever reported, strongly supporting the policy that women 40 years and older who are negative for 14 high-risk HPV types can be safely screened in another 10 years," Harper said.

"These data need to be incorporated into U.S. policy for quality measures and payment reform."

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